TY - JOUR
T1 - Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
AU - Zheng, Tenghao
AU - Roda, Giulia
AU - Zabana, Yamile
AU - Escudero-Hernández, Celia
AU - Liu, Xingrong
AU - Chen, Ye
AU - Camargo Tavares, Leticia
AU - Bonfiglio, Ferdinando
AU - Mellander, Marie-Rose
AU - Janczewska, Izabella
AU - Vigren, Lina
AU - Sjöberg, Klas
AU - Ohlsson, Bodil
AU - Almer, Sven
AU - Halfvarson, Jonas
AU - Miehlke, Stephan
AU - Madisch, Ahmed
AU - Lieb, Wolfgang
AU - Kupcinskas, Juozas
AU - Weersma, Rinse K
AU - Bujanda, Luis
AU - Julià, Antonio
AU - Marsal, Sara
AU - Esteve, Maria
AU - Guagnozzi, Danila
AU - Fernández-Bañares, Fernando
AU - Ferrer, Carmen
AU - Peter, Inga
AU - Ludvigsson, Jonas F
AU - Pardi, Darrell
AU - Verhaegh, Bas
AU - Jonkers, Daisy
AU - Pierik, Marieke
AU - Münch, Andreas
AU - Franke, Andre
AU - Bresso, Francesca
AU - Khalili, Hamed
AU - Colombel, Jean-Frederic
AU - D'Amato, Mauro
AU - MC-Europe GETECCU GWAS group
PY - 2024/3/1
Y1 - 2024/3/1
N2 - BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
AB - BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
KW - GWAS
KW - HLA
KW - Microscopic colitis
KW - collagenous colitis
KW - genetics
U2 - 10.1093/ecco-jcc/jjad165
DO - 10.1093/ecco-jcc/jjad165
M3 - Article
SN - 1873-9946
VL - 18
SP - 349
EP - 359
JO - Journal of Crohn's & Colitis
JF - Journal of Crohn's & Colitis
IS - 3
M1 - jjad165
ER -